Effects of HMGB1 on Tricellular Tight Junctions via TGF-β Signaling in Human Nasal Epithelial Cells

Abstract

The airway epithelium of the human nasal mucosa acts as a physical barrier that protects against inhaled substances and pathogens via bicellular and tricellular tight junctions (bTJs and tTJs) including claudins, angulin-1/LSR and tricellulin. High mobility group box-1 (HMGB1) increased by TGF-β1 is involved in the induction of nasal inflammation and injury in patients with allergic rhinitis, chronic rhinosinusitis, and eosinophilic chronic rhinosinusitis. However, the detailed mechanisms by which this occurs remain unknown. In the present study, to investigate how HMGB1 affects the barrier of normal human nasal epithelial cells, 2D and 2.5D Matrigel culture of primary cultured human nasal epithelial cells were pretreated with TGF-β type I receptor kinase inhibitor EW-7197 before treatment with HMGB1. Knockdown of angulin-1/LSR downregulated the epithelial barrier. Treatment with EW-7197 decreased angulin-1/LSR and concentrated the expression at tTJs from bTJs and increased the epithelial barrier. Treatment with a binder to angulin-1/LSR angubindin-1 decreased angulin-1/LSR and the epithelial barrier. Treatment with HMGB1 decreased angulin-1/LSR and the epithelial barrier. In 2.5D Matrigel culture, treatment with HMGB1 induced permeability of FITC-dextran (FD-4) into the lumen. Pretreatment with EW-7197 prevented the effects of HMGB1. HMGB1 disrupted the angulin-1/LSR-dependent epithelial permeability barriers of HNECs via TGF-β signaling in HNECs.

International consensus statement on allergy and rhinology: Allergic rhinitis – 2023

“…AR derived nasal secretions and histamine are strong disruptors of the epithelial barrier function 600 . Very recently, high mobility group box‐1 (HMGB1), which is increased by transforming growth factor (TGF)‐β1 in AR, was shown to disrupt the epithelial barrier by decreasing angulin‐1/LSR (lipolysis‐stimulated lipoprotein receptor) in vitro in human nasal epithelial cell cultures 601 . Even particulate matter (PM)‐2.5, a very fine particle found in air pollution, affects the epithelial barrier in an AR mouse model by reducing ZO‐1 expression 602 .…”

Atypical Macropinocytosis Contributes to Malignant Progression: A Review of Recent Evidence in Endometrioid Endometrial Cancer Cells

“…TGF-β is associated with increased migration and malignant transformation of endometrial carcinomas through activation of estrogen-related receptor alpha (ERRα); it is also associated with invasion and epithelial-to-mesenchymal transition (EMT) [ 64 ]. TGF-β increases HMGB1 expression and induces changes in LSR localization and downregulation, resulting in reduced epithelial barrier homeostasis [ 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ]. TGF-β levels are also elevated in high-grade stages of endometriosis [ 73 ].…”